Management of individuals with germline pathogenic/ likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Purpose: Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited. Methods: An international workgroup developed guidance on clinical management of CHEK2 heterozygotes informed by peer-reviewed publications from PubMed. Results: Although CHEK2 is considered a moderate penetrance gene, cancer risks may be considered as a continuous variable, which are influenced by family history and other modifiers. Consequently, early cancer detection and prevention for CHEK2 heterozygotes should be guided by personalized risk estimates. Such estimates may result in both downgrading lifetime breast cancer risks to those similar to the general population or upgrading lifetime risk to a level at which CHEK2 heterozygotes are offered high-risk breast surveillance according to country-specific guidelines. Risk-reducing mastectomy should be guided by personalized risk estimates and shared decision making. Colorectal and prostate cancer surveillance should be considered based on assessment of family history. For CHEK2 heterozygotes who develop cancer, no specific targeted medical treatment is recommended at this time.Conclusion: Systematic prospective data collection is needed to establish the spectrum of CHEK2-associated cancer risks and to determine yet-unanswered questions, such as the outcomes of surveillance, response to cancer treatment, and survival after cancer diagnosis.(c) 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

Despite the well-known role of CHEK2 germline pathogenic variants in cancer predisposition, there are limited resources for managing CHEK2 heterozygotes in clinical practice. The guidance on clinical management of CHEK2 heterozygotes should be personalized based on risk estimates considering family history and other modifiers. Risk-reducing mastectomy and cancer surveillance should be considered according to personalized risk estimates and shared decision making. Further research is needed to establish the spectrum of CHEK2-associated cancer risks and the outcomes of surveillance, response to treatment, and survival.